TY - JOUR
AU - Georgiou, Irene
AU - Robinson, Colin
AU - O'Byrne, Sean N.
AU - Matsuda, Alex
AU - Grygier, Przemysław
AU - Smith, Craig D.
AU - O'Neill, Sandra
AU - Ahmad, Shamshad A.
AU - Norval, Suzanne
AU - Post, John M.
AU - Groenewold, G. J. Mirjam
AU - Urakova, Nadya
AU - Wanningen, Patrick
AU - Kresik, Leanid
AU - Plewka, Jacek
AU - Delpal, Adrien
AU - See, Kexin
AU - Eadsforth, Thomas
AU - Wierzbicka, Kinga
AU - Decroly, Etienne
AU - Saikatendu, Kumar Singh
AU - Chang, Edcon
AU - Snijder, Eric J.
AU - Pyrć, Krzysztof
AU - Czarna, Anna
AU - Scott, Duncan
AU - Gilbert, Ian H.
PY - 2026
DA - January
TI - Crystallographic characterisation and development of bi-substrate inhibitors of coronavirus nsp14 methyltransferase
JO - RSC Medicinal Chemistry
DO - https://doi.org/10.1039/d5md00896d
AB - SARS-CoV-2 non-structural protein 14 (nsp14) is essential for viral mRNA cap guanine-N7 methylation and represents a promising but underexplored antiviral target. Herein we describe a structure-guided campaign based on a hit from a focussed SAM mimetic library. Systematic SAR exploration guided by six X-ray co-crystal structures in complex with SARS-CoV-2 led to compound 26, a bi-substrate inhibitor that bridges the SAM and RNA cap binding sites. Compound 26 achieved nanomolar potency against nsp14 from SARS-CoV-2 (IC₅₀ = 53 nM), SARS-CoV-1, and two alphacoronaviruses, with excellent selectivity over human RNMT and flaviviral MTase. In general, the compounds demonstrated favourable metabolic stability, passive permeability, and no HepG2 cytotoxicity. However, cellular antiviral activity was limited, revealing disconnects between enzyme inhibition and phenotypic response. These findings provide a structural framework for optimizing bi-substrate methyltransferase inhibitors against coronaviruses with a view for pan-coronaviral activity.
PB - Royal Society of Chemistry
UR - https://discovery.dundee.ac.uk/en/publications/73eb15e1-f80d-48a6-ba31-3b4818123f33
KW - Coronavirus (COVID-19)
ER